As a result of work in our laboratory with the hamster model, it is possible to address the following set of hypotheses concerning the etiology and prevention of the neural tube closure defects (NTCD), cranium bifidum (CB) and spinal bifida (SB): 1) maternal serum folic acid (FA) level in the hamster is correlated with the frequency of NTCD at 9 days of gestation; 2) preconceptually induced FA deficiency is correlated with increased frequencies, while FA supplementation at some dose is correlated with decreased frequencies; 3) some doses of FA are teratogenic; 4) diphenlhydantoin has similar effects on the developing hamster as FA deficiency: a decrease in serum folate levels and an increase in NTCD; 5) supplementation of FA reduces the effects of diphenylhydantoin. Heritability for these defects is only 4 percent, based on 59 litters, indicating that the variance in defect frequencies in this model might be largely environmental. Heritability for susceptibility to methyl salicylate induced NTCD is only 9 percent (based on 100 litters). This animal model is ideal for attempting to decrease the liability for these defects. From more preliminary studies, we know that animals held on a folic acid deficient diet for 2 weeks prior to mating have a significantly higher rate of resorptions (30 percent vs. 5 percent for controls) and NTCD (37 percent vs 17 percent for controls) at 9 days of gestation. Animals receiving daily subcutaneous injections of FA for 2 weeks prior to mating show either an increase in the frequency of NTCD or a DECREASE in the frequency of NTCD depending on the dosage used (0.0005 mg FA/100, body weight vs. 0.1 mg FA). By conducting additional studies using a greater number of animals and monitoring maternal serum folic acid levels via radioimmunoassay of pregnant and non pregnant animals, it is hoped that the above stated 5 hypotheses will acquire additional support.